Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice

Marco Heestermans, Salam Salloum-Asfar, Daniela Salvatori, El Houari Laghmani, Brenda M. Luken, Sacha S. Zeerleder, Henri M. H. Spronk, Suzanne J. Korporaal, Gerry T. M. Wagenaar, Pieter H. Reitsma, Bart J. M. van Vlijmen*

*Corresponding author for this work

Research output: Contribution to journalErratum / corrigendum / retractionsAcademic

23 Citations (Web of Science)

Abstract

Recently, platelets, neutrophils, and factor XII (FXII) have been implicated as important players in the pathophysiology of venous thrombosis. Their role became evident in mouse models in which surgical handling was used to provoke thrombosis. Inhibiting anticoagulation in mice by using small interfering RNA (siRNA) targeting Serpinc1 and Proc also results in a thrombotic phenotype, which is spontaneous (no additional triggers) and reproducibly results in clots in the large veins of the head and fibrin deposition in the liver. This thrombotic phenotype is fatal but can be fully rescued by thrombin inhibition. The mouse model was used in this study to investigate the role of platelets, neutrophils, and FXII. After administration of siRNAs targeting Serpinc1 and Proc, antibody-mediated depletion of platelets fully abrogated the clinical features as well as microscopic aspects in the head. This was corroborated by strongly reduced fibrin deposition in the liver. Whereas neutrophils were abundant in siRNA-triggered thrombotic lesions, antibody-mediated depletion of circulating Ly6G-positive neutrophils did not affect onset, severity, or thrombus morphology. In addition, absence of circulating neutrophils did not affect quantitative liver fibrin deposition. Remarkably, siRNA-mediated depletion of plasma FXII accelerated the onset of the clinical phenotype; mice were affected with more severe thrombotic lesions. To summarize, in this study, onset and severity of the thrombotic phenotype are dependent on the presence of platelets but not circulating neutrophils. Unexpectedly, FXII has a protective effect. This study challenges the proposed roles of neutrophils and FXII in venous thrombosis pathophysiology.
Original languageEnglish
Pages (from-to)2630-2637
JournalBlood
Volume127
Issue number21
DOIs
Publication statusPublished - 26 May 2016

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